We have investigated proto-oncogene activation in chemical-induced and spontaneous rodent tumors as well as some types of human tumors. Induction of tumors in rodents by genotoxic carcinogens results in activation of specific oncogenes with high frequency. For example the activation of K-ras oncogene is one important mutational event in the development of pulmonary adenocarcinoma in both human and rodent tumors. Activated K-ras genes have been detected at a high frequency in both spontaneously occurring and chemical induced lung tumors from rodents. Chemical induced tumors examined include those derived from treatment with 1,3-butadiene, tetranitromethane, methylene chloride, benzo(a)pyrene, urethane and NNK (a tobacco specific nitrosamine). Activated K-ras genes have been detected in 40% of human pulmonary adenocarcinomas. In addition, N-ras, H-ras and two uncharacterized oncogenes have been detected in both adenocarcinomas and squamous cell carcinomas by the nude mouse tumorigenicity assay; 12 of 14 human lung tumors examined tested positive. Clones of fragments of the unknown genes have been isolated and considerable progress has been made in sequencing these fragments. In addition an activated H-ras detected in a squamous cell carcinoma does not contain activated lesions in the coding region of the H-ras gene. The data suggests that the oncogene lesion resides in the regulatory region of the gene and attempts are underway to find it. A novel type of mutational activation has also been characterized in K-ras oncogene detected in a spontaneous mouse lung tumor and in two mouse liver tumors induced by furan. Thirty base pair inserts in the second exon of K-ras were observed in these tumors. These inserts lead to tandem repeats in the K-ras gene. Examination of proto-oncogene activation in mouse tumors induced by various environmental and occupational carcinogens (i.e., methylene chloride, chlordane, tetrachloroethylene, trichloroethylene) in both susceptible and resistant strains is also in progress. These approaches may enable us to more accurately estimate risk of cancer in humans exposed to specific classes of carcinogens.